Antibody-drug conjugates in gynecologic malignancies: breakthroughs, challenges, and future directions

Gynecologic malignancies - principally cervical cancer (CC), endometrial carcinoma (EC), and ovarian cancer (OC) - have been managed with conventional modalities including surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy, yielding modest overall outcomes. The scarcity of effective later-line options has fueled rapid advances in antibody-drug conjugate (ADC) research. Precision-targeted, highly potent ADCs hold the promise of improving outcomes for patients with gynecologic tumors. To date, multiple ADCs directed against antigens such as tissue factor (TF), human epidermal growth factor receptor 2 (HER2), trophoblast cell-surface antigen 2 (Trop2), and folate receptor alpha (FRα) have entered clinical trials or received regulatory approval for CC, EC, and OC. These agents have demonstrated superiority over conventional chemotherapy in patients with recurrent or metastatic disease, with particularly pronounced efficacy in populations exhibiting high target expression. Nevertheless, clinical translation remains challenged by response heterogeneity attributable to tumor heterogeneity, the emergence of resistance mechanisms, and class-specific adverse events including ocular toxicity, interstitial lung disease (ILD), hepatotoxicity, and peripheral neuropathy. Continued refinement of next-generation ADC platforms - encompassing bispecific ADCs, dual-payload ADCs, peptide-drug conjugates (PDCs), and radionuclide-conjugated drugs - is anticipated to overcome current limitations and deliver superior oncologic outcomes.